Date Published: January 25, 2011
Publisher: Public Library of Science
Abstract: The Malaria Eradication Research Agenda (malERA) consultative group on Basic Science and Enabling Technologies present a research and development agenda for basic research required for malaria eradication.
Partial Text: The current malaria control effort has focused on developing existing products and procedures (for example, drugs and the distribution of bednets) to reduce malaria morbidity and mortality. However, it is commonly accepted that eradication will not be achieved with current tools. Thus, we must now accelerate the development of a new generation of tools and knowledge aimed specifically at malaria eradication. As we look towards this ambitious goal, we must recognize that cutting-edge basic science, novel research strategies, and creative multidisciplinary approaches all need to be mobilized to bridge the gap between bench, preclinical, clinical, and population-based sciences. The malaria science community is now at a turning point where major advances are needed to move the field forward from control towards the goal of global malaria eradication.
The development of Plasmodium in vitro culture systems that encompass the entire parasite life cycle of P. falciparum and P. vivax is critical for efforts to develop new vaccines, drugs, diagnostic tests, and challenge/test systems for clinical trials. The development of such systems will require a sustained community-wide collaborative effort and a long-term commitment. Specific stages of the life cycle for human malaria parasites that remain key priorities for in vitro culture development are sporogony, sustained blood-stage culture for P. vivax, and the pre-erythrocytic liver stage.
Not every aspect of parasite biology can be studied using in vitro culture. In some cases, whole animal models will be needed. For example, validated biomarkers for intrahepatic development and markers of past infection that could help distinguish between new infection and relapse will be important during elimination and can only be identified in whole animal models ,. Data from primate studies could provide an interim platform for developing novel diagnostics that could inform future work in parallel with in vitro models –. Mechanisms to support cross-institute/laboratory collaborations and access to the few centres with expertise and resources in primate/malaria research would facilitate and enhance a wide range of essential research.
Major advances towards understanding fundamental aspects of model organisms inherently follow technological innovations that move fields in new directions. Thus, the ability to manipulate the genomes of different Plasmodium species has revolutionized malaria research. Nevertheless, we are still a long way from the systematic use of reverse genetics seen in other model systems such as yeast. For example, although the P. falciparum genome was completed more than 5 years ago, as many as half of the annotated genes are still listed as having a hypothetical or unknown function; around 90% of the genes have little biological evidence for function. Furthermore, little is being done currently to coordinate the study of individual genes or gene families, with the exception of recent efforts to systematically define the function of proteins involved in erythrocyte remodeling and export .
As with genomic innovations, new technological platforms that permit the deep characterization of the metabolome (complete set of small-molecule metabolites) of Plasmodium will identify new potentially druggable targets ,. Indeed, analysis of the parasite’s metabolome is already revealing profound new insights into parasite biology that were not amenable to or that were missed by genomic approaches –. For metabolites that are readily identifiable, differences among parasite strains, under varying drug conditions, or in mutant backgrounds will enhance understanding of the known metabolic pathways present in Plasmodium spp. However, many of the measurable compounds are likely to derive from previously undetected novel metabolites (including the products of poorly understood lipid and carbohydrate metabolism). The identification of these compounds could yield key insights for the development of new antimalarial drugs or the control of drug resistance. Moreover, the identification of the metabolic similarities between different parasite stages could provide new approaches to the development of drugs with potential to kill the parasites at many points in their life cycle, possibly in both the human host and the mosquito vector –.
The emergence of artemisinin resistance , and changes in the interrelationships of humans, mosquitoes, and parasites as elimination proceeds will produce unexpected new challenges. The Consultative Group, therefore, considered it a priority to establish information systems for monitoring the changes in epidemiology, pathology, and host-parasite-vector interactions that result from intensified control and burgeoning elimination efforts so that basic research can react in a timely manner to changing circumstances (see also ,).
No campaign for the control or elimination of malaria can proceed without a detailed appreciation of the epidemiology of the disease and of host-parasite-vector interactions. As increasing parts of the world move towards elimination, a deeper understanding of the basic science of host-parasite-vector population interactions in disease transmission and of the changes in these interactions that result from intensified control and elimination efforts will be increasingly important .
Strategies aimed at decreasing mosquito life span are predicted to impact upon transmission (see also ,). Research that investigates the parasite stages that develop within the mosquito and their transmission through the vector is likely to be of great use, therefore, in malaria control and eradication. Focused research efforts designed to understand the epidemiology of the gametocyte and how it varies with species, with host, and with the environment are required. Insights arising from such research will be critical for determining the driving factors for new human and mosquito infections, and manipulation of these factors will open up new avenues for targeting the key parasite regulatory switches that occur when a parasite undergoes a transition event. Importantly, however, such a focus on transmission need not necessarily be aimed at finding a magic bullet—a compound that can work against all parasite stages in all hosts. Instead, there will be significant utility in developing several inhibitors with similar pharmacokinetic and pharmacodynamic profiles that affect different metabolic pathways and stages in a combined drug treatment regimen. For now, the absence of compounds that preferentially affect gametocytogenesis, gamete-ookinete, or ookinete-oocyst transition as well as the lack of understanding of the mechanism of action for those very few currently available compounds highlights the need for renewed efforts in this area .
From our discussions, we propose a basic science research and development agenda for malaria eradication (Box 2) that will hopefully yield new interventions that are not hindered by the current drug resistance status of the parasites or by changes in environmental and host factors.